We have investigated the mechanisms of oncogene regulation in human malignancies. A large body of evidence has implicated the c-myc oncogene in normal cell growth and differentiation as well as in the development of a wide range of human cancers. This project is designed to study both the mechanisms of transcriptional regulation of the c-myc gene and to determine the role of c-Myc protein in the development of neoplastic disease. The major subprojects are the following: A) Transcriptional regulation of the c-myc oncogene in normal and neoplastic cells. We have identified several discrete protein binding sites within the c-myc gene designated as myc intron factor-1 (MIF-1), MIF-2, and MIF-3. Cloning and characterization of these transcription factors would allow us to establish their role in the regulation of c-myc oncogene expression in normal and cancer cells. B) Effect of pharmacological agents on the function of transcription factors and their role in the regulation of the c-myc gene. We are interested in developing agents which can selectively modulate oncogene expression and to establish their relation to differentiation and cell proliferation. C) The role of the c-Myc protein in normal and neoplastic growth. The product of the c-myc gene is a nuclear phosphoprotein that has been implicated in cell differentiation, apoptosis, and in the development of human tumors. c-Myc functions as a transcription factor, however, the mechanism of c-myc regulation remains unknown. We have established that c- myc associates with microtubules in in vivo and in in vitro, and we plan to determine the involvement of microtubules in regulation of c-Myc transcriptional activity and is possible role in the neoplastic disease.